ABSTRACT The goal of this R01 application is to improve the treatment of atherosclerosis and endovascular stenting by illuminating their underlying pathobiology through translatable intravascular imaging of arterial inflammation and structure. To achieve this goal, we will engineer a next-generation intravascular near-infrared fluorescence-intravascular ultrasound (NIRF-IVUS) imaging system targeted to human coronary arteries. We will then harness NIRF-IVUS to elucidate the role of inflammation in assessing and guiding atherosclerosis and stent restenosis pharmacotherapeutic strategies. Coronary artery disease (CAD) is a worldwide leading cause of death and disability, and often requires coronary stenting for treatment. Biological and molecular processes such as inflammation drive devastating CAD and stent complications, but are largely invisible to contemporary clinical imaging methods. The ability to image and quantify coronary arterial molecular processes such as inflammation would improve patient risk stratification, guide the selection CAD and stent pharmacotherapies, and help streamline CAD and stent therapeutics development from phase 0 /preclinical to phase IV/post-approval stages. Our laboratory has co-developed novel and innovative intravascular imaging systems that combine high- resolution IVUS, the dominant intracoronary structural imaging method, with NIRF molecular imaging, a powerful new molecular imaging approach under rapid clinical translation. In this application, we will substantially improve the translational potential of intravascular NIRF-IVUS to detect high-risk plaques and stents at risk of complications, and further guide the personalized selection of arterial pharmacotherapy. The Specific Aims of this proposal are: Aim 1: Develop a next generation NIRF-IVUS v2.0 system optimized for in vivo intracoronary imaging, and test in vivo in a swine serial coronary stent inflammation model. Aim 2: Demonstrate that NIRF-IVUS measures of inflammation drive atheroma progression and atherothrombosis in vivo, and predict the response to ezetimibe, an FDA-approved atherosclerosis agent. Aim 3: Demonstrate that NIRF-IVUS measures of inflammation drive stent restenosis in vivo, and predict the response to colchicine, an FDA-approved therapy with the potential to reduce restenosis. The long-term objectives of this research are to provide a translational foundation for clinical NIRF-IVUS, and to provide a new, personalized medicine approach to select patients for anti-inflammatory therapy to reduce plaque progression, atherothrombosis, and stent complications. Clinical translation of this knowledge may provide a new paradigm using intravascular NIRF-IVUS to improve outcomes in patients with CAD.